Multiple Sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease of the human central nervous system. MS affects over 2.0 million individuals worldwide and is the major cause of non-traumatic neurological disability in young adults in the United States. The classical view of MS as a myelin and white matter disease has been extended to include axonal transection, cortical demyelination and neuronal degeneration. While the clinical impact of gray matter pathology in MS brains is unknown, greater than 50% of MS patients are cognitively impaired. There is minimal or no correlation between physical disability and cognitive dysfunction in MS patients. Although focal hippocampal pathology causes cognitive dysfunction in several CNS diseases, the hippocampus has received little attention in MS research. The overall goal of the proposal is to determine if hippocampal changes contribute to episodic memory loss and cognitive decline in MS patients. Our studies are based upon the hypothesis that hippocampal demyelination reduces synaptic plasticity and causes episodic memory dysfunction. Preliminary studies identify significant hippocampal demyelination and alterations in hippocampal gene transcripts that facilitate memory and learning. Our studies are translational, MS patient based and divided into three specific aims. The first aim will determine if memory impaired MS patients have characteristic hippocampal pathology as determined by MRI. Preliminary studies suggest that diffusion tensor imaging (DTI) measures of the fornix will provide reliable and non-invasive surrogate markers for the episodic memory impairment in MS patients. The second aim will characterize hippocampal demyelination and neuronal pathology in MS hippocampi and establish pathological correlates of MRI alterations with hippocampus and fornix obtained by rapid autopsy of MS patients. The third aim will define molecular mechanisms of hippocampal dysfunction in MS patients. Preliminary studies support the hypothesis that hippocampal demyelination decreases delivery of synaptic vesicles to presynaptic terminals. This will reduce the glutamate and Ca entry into post synaptic terminals and decrease second messenger signally that facilitates hippocampal memory function in MS patients. Collectively, this proposal presents an integrated multi-disciplinary approach designed to elucidate causes of memory dysfunction in MS patients. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS) afflicts over 2 million individuals worldwide and is a major cause of neurological disability in the USA. Most MS research investigates the cause of physical disability in MS patients. Despite the fact that over half of MS patients have reduced memory function, very little research has been performed on the cause of memory loss in MS patients. This is surprising as memory loss is a major contributor to unemployment of MS patients. Research in this proposal will determine the causes of reduced memory function in MS patients. We will study MS patients with reduced memory, develop brain imaging techniques to identify MS patients at risk for memory problems and identify ways to treat MS patients with memory loss. [unreadable] [unreadable] [unreadable]